Characterization of circumferential antral pulmonary vein isolation areas resulting from pulsed-field catheter ablation

Abstract Aims The cornerstone of pulmonary vein (PV) isolation (PVI) is a wide-area circumferential ablation (WACA) resulting in an antral PVI area. Pulsed-field ablation (PFA) is a new nonthermal ‘single-shot’ PVI technique resulting in well-characterized posterior isolation areas. However, information on circumferential PVI area is lacking. Thus, we sought to characterize the circumferential antral PVI areas after PFA-PVI. Methods and results Atrial fibrillation (AF) patients underwent fluoroscopy-guided PVI with a pentaspline PFA catheter. Ultra-high-density voltage maps using a 20-polar circular mapping catheter were created before and immediately after PVI to identify and quantify (i) insufficient isolation areas per antral PV segment (10-segment model) and (ii) enlarged left atrial (LA) isolation areas (beyond the antral PV segments) per LA region (8-region model). The PFA-PVI with pre- (5469 ± 1822 points) and post-mapping (6809 ± 2769 points) was performed in 40 consecutive patients [age 62 ± 6 years, 25/40 (62.5%) paroxysmal AF]. Insufficient isolation areas were located most frequently in the anterior antral PV segments of the left PVs (62.5–77.5% of patients) with the largest extent (median ≥0.4 cm2) located in the same segments (segments 2/5/8). Enlarged LA isolation areas were located most frequently and most extensively on the posterior wall and roof region (89.5–100% of patients; median 1.1–2.7 cm2 per region). Conclusion Fluoroscopy-guided PFA-PVI frequently results in insufficient isolation areas in the left anterior antral PV segments and enlarged LA isolation areas on the posterior wall/roof, which both may be extensive. To optimize the procedure, full integration of PFA catheter visualization into three-dimensional-mapping systems is needed.


What's new?
• Following fluoroscopy-guided pulmonary vein (PV) isolation (PVI) using pulsed-field ablation (PFA), ultra-high-density voltage maps post-PFA were created to characterize the resulting circumferential isolation area [insufficient PV antral and enlarged left atrial (LA) isolation area].
• Insufficient antral isolation occurred most frequently in anterior antral PV segments.
• The largest extent of insufficient antral isolation areas was found in the same location, but also in the anterior lower segment of the right inferior PV.
• Enlarged LA isolation areas were located most frequently and most extensively on the posterior wall and roof region of both LA sides.

Introduction
The cornerstone of catheter ablation for atrial fibrillation (AF) is to achieve complete antral pulmonary vein isolation (PVI). 1 Regardless of the technique used, the approach should be to create a circumferential isolation area specifically encompassing the antral segments of the pulmonary veins (PVs), 1 since they frequently contain sites of AF initiation and/or maintenance. Accordingly, the effectiveness of creating a large antral isolation area [wide-area circumferential ablation (WACA)] to significantly lower AF recurrence rates has been confirmed in multiple studies. 2,3 To achieve PVI fast and effectively, various 'single-shot' devices were developed, including high-intensity focused ultrasound balloon, laserballoon, and cryoballoon, of which the latter is currently the most commonly used. All of these mainly fluoroscopically guided single-shot techniques had their circumferential or at least posterior isolation area characterized. [4][5][6] Pulsed-field ablation (PFA) is a new technology for cardiac catheter ablation using a nonthermal energy source, which has previously been shown to be both safe and effective. 7,8 Efforts to define the PVI area resulting from single-shot PFA have been made, but are limited to the posterior PV antrum and the adjacent posterior wall (PW). 9,10 The purpose of this study was to characterize the circumferential PVI area created by a single-shot pentaspline PFA catheter (Farawave™; Farapulse Inc., Menlo Park, CA, USA). Thus, we investigated ultra-high-density maps, acquired pre-and post-PFA-PVI, regarding frequency (qualitative analysis) and extent (quantitative analysis) of insufficient PV antral and enlarged left atrial (LA) isolation areas.

Methods
This was an observational, single-centre, investigator-initiated study. The work flow of the mapping and ablation procedures, as described in the following subsections, were standard of care during the selected period (September to November 2021). Analysis of the ultra-high-density maps was performed retrospectively. The study population consisted of 40 consecutive patients with paroxysmal or persistent AF who underwent their first catheter ablation procedure for antral PVI using PFA. The study protocol was reviewed and approved by our institutional review board (registration number 21-1728). All patients gave written informed consent.
Patients returned for follow-up visits in our outpatient clinic at 3 and 6 months and were assessed for arrhythmia recurrence via history, 12-lead electrocardiogram (ECG), 24 h Holter ECG, and ECGs/rhythm strips recorded at another hospital. Any antiarrhythmic drug therapy was stopped 3-month postablation. Arrhythmia recurrence was defined as documented AF, atrial flutter, or atrial tachycardia lasting longer than 30 s.

Pulsed-field catheter ablation
The PFA system 7,8,11 as well as the standard catheter ablation procedure including catheter placement and LA mapping have been described in detail. 2 In brief, after acquiring the pre-PFA map, the sheath and mapping catheter were exchanged for a 13-F steerable sheath (Faradrive™; Farapulse Inc.) and a 31 or 35 mm size 12-F over-the-wire pentaspline PFA catheter (Farawave™; Farapulse Inc.). To deploy the pentaspline PFA catheter in the desired shape and to advance it into the desired antral PV area, fluoroscopy in conjunction with the three-dimensional (3D) anatomic pre-PFA map including the visualized PFA catheter electrodes was used. Baseline electrical potentials were recorded on the PFA catheter from all PVs. The PVI was performed with four paired applications (generator output 2.0 kV) per vein, resulting in two applications each in the flower and basket configuration. 7,12 Between a pair of applications, the catheter was rotated once by 30° to assure a dense circumferential isolation area. In patients with a left common os, the superior and inferior PV branches were treated separately. Subsequently, PVI was assessed by electrograms recorded on the PFA catheter. In case of persistent PV conduction or persistent antral electrograms, additional lesions were permitted per operator discretion.
At the end of the procedure, PVI was confirmed with the 20-polar circular mapping catheter (Lasso®; Biosense Webster, USA, spacing 2-6-2, electrode size 1 mm) by demonstration of entrance and exit block. Additionally, dormant conduction with adenosine was tested. Importantly, if PVI was confirmed, no further lesions were applied regardless of any insufficient isolation revealed by the post-PFA voltage map.

Ultra-high-density mapping
Before and after PFA-PVI, an ultra-high-density fast electroanatomic map of the LA was acquired using a 20-polar circular mapping catheter and the CARTO® 3D electroanatomic mapping system (CARTO® 3 System; Biosense Webster). In order to achieve high accuracy for electrogram acquisition, mapping was standardized utilizing the CARTO® CONFIDENSE™ module (Supplementary material online, Table S1). To assure precise anatomical and electrical delineation of the LA ridge, the LA appendage was explicitly not included in the maps.

Analysis of ultra-high-density maps
The following definitions were used: First, the PV ostium was defined as the point of maximal inflection between the PV wall and the LA wall. 6,13 Second, the PV antrum was defined as the circumferential area beginning at the PV ostium and reaching 5 mm into the LA. 14 Third, modified from the EFFICAS I study, 15 a 10-segment model for the left and right PV antral area was created (Supplementary material online, Figure S1). Forth, an eight-region model for the LA was created (Supplementary material online, Figures S2 and S3). Fifth, for the purpose of comparison with previous studies, 5,6 a peak-to-peak bipolar electrogram amplitude <0.5 mV during sinus rhythm was defined as isolation threshold. Thus, an insufficient antral PVI area was defined by a bipolar electrogram amplitude ≥0.5 mV within the antral PV segments and an enlarged LA isolation area was defined by a bipolar electrogram amplitude <0.5 mV within the LA beyond the antral PV segments.
An anatomical map without voltage data was used to outline the PV ostia, the antral PV segments (10-segment model) and the LA regions (8-region model). Thereafter, voltage data were visualized and the relevant electrograms were reviewed to assure exclusion of far-field signals, for example, of the LA appendage.
After completion, the insufficient isolation area per antral PV segment and the enlarged isolation area per LA region were measured. For each PV segment and LA region, the total area was measured as well. To further facilitate comparison with previously published data, the circumferential PVI area, total PW area, PW-PVI area, and nonablated PW area were calculated (Supplementary material online, Table S2).
A minimum surface area of 0.1 cm 2 was deemed relevant and thus included in the analysis. For the assessment of enlarged LA isolation areas, both maps (pre-and post-PFA) had to be acquired in sinus rhythm or atrial pacing from the distal coronary sinus (CS) to allow reliable identification of pre-existing low-voltage areas (LVAs). All measurements were made with the CARTO® 3 software, using the 'design line' or 'area measurement' tool.

Statistical analysis
Categorical variables are expressed as number (percentage). Continuous variables are expressed as mean ± standard deviation or median (interquartile range) as appropriate.
Within group differences were assessed using a McNemar's test, a Wilcoxon signed rank test, or an unpaired T test. Between group differences were assessed using a χ 2 test, a Mann-Whitney U test, or a twosample T test as appropriate. All tests were two-sided, and a P-value of <0.05 was considered statistically significant. The SPSS Statistics 25 (IBM Corporation, Armonk, NY, USA) was used for statistical analysis.
In 31/40 (77.5%) patients, the 31 mm size pentaspline PFA catheter was selected due to a maximum PV diameter of 25 (23-26) mm. Accordingly, in 9/40 (22.5%) patients, the 35 mm size PFA catheter was chosen due to a maximum PV diameter of 30 (26-32) mm (P = 0.003). The average number of PFA applications was 8.7 for the left superior pulmonary vein (LSPV), 8.1 for the left inferior pulmonary vein (LIPV), 8.5 for the right superior pulmonary vein, and 8.4 for the right inferior pulmonary vein (RIPV). Acute reconnection of a PV occurred only in one patient (LSPV). This PV received a second set of eight PFA applications and was thereafter isolated.

Insufficient isolation areas: frequency (qualitative analysis)
All 160 PVs were isolated at the end of the procedure, demonstrating entrance block, exit block, and absence of dormant conduction using adenosine. Of these, 48 (30%) PVs showed a sufficient isolation in all 5 antral segments. Conversely, the remaining 112 (70%) PVs demonstrated insufficient isolation in at least one antral segment.
One-third of the overall antral PV segments had an insufficient isolation area of at least 0.1 cm 2 [270/800 (33.75%) antral PV segments]. Furthermore, on the left side, the presence of insufficient isolation areas within the antral PV segments did depend strongly upon their location (Table 2, Figure 1). The highest rates were seen on the anterior antral PV segments (S) of the LSPV and LIPV (S 2/4/6/8; examples Figure 2A and B). On the other hand, the lowest rates (2.5-7.5%) were seen on the posterior antral PV segments of the LIPV and lower LSPV (S 5/7/9). Indeed, the anterior antral PV segments showed significantly higher rates of insufficient isolation areas than the posterior antral PV segments (P = 0.019, P < 0.001, P < 0.001, P < 0.001; Table 2

Insufficient isolation areas: extent (quantitative analysis)
Antral PV segments having a median of at least 0.4 cm 2 of insufficient isolation area were almost exclusively located at the anterior aspect of the left PVs (S 2/4/8; Table 3, Figure 3A and B). The only exception is the anterior lower antral PV segment of the right inferior PV (S 8).

Enlarged isolation areas: frequency (qualitative analysis)
The PW and roof region of both LA sides were the most frequent locations of enlarged LA isolation areas ( Table 2, example Figure 2D). For the left LA, all [38 (100%)] patients showed enlarged isolation areas on the PW and almost all [37/38 (97.4%)] patients showed enlarged isolation areas on the roof. When comparing the opposing walls on the left LA side, the PW (100%) and roof (97.4%) were significantly more likely to show enlarged isolation areas than the anterior wall (52.6%) and sidewall (50.0%), respectively (both P < 0.001). For the right LA side, again, the PW (92.1%) was significantly more likely to show enlarged isolation areas than the anterior wall (68.4%; P = 0.004).
Comparison of the opposing walls for the left-sided LA showed significantly larger LA isolation areas on the roof than on the sidewall, and similarly, significantly larger LA isolation areas on the PW than on the anterior wall (both P < 0.001; Table 3, Figure 4). For the right LA side, significantly larger LA isolation areas on the PW than on the anterior wall were seen (P = 0.002; Table 3).

Extent of circumferential and posterior wall isolation areas
The circumferential PVI area for both LA sides was 22.2 ± 5.6 cm 2 ( Table 3). Between left-and right-sided LA, the circumferential PVI area did not differ significantly (P = 0.676). For the total PW area, the PW-PVI area, and the nonablated PW area, a significant difference between right and left LA sides was found (P = 0.015, P < 0.001, P = 0.001; Table 3).

Follow-up and arrhythmia recurrence
A median of 190 days (167-202 days) of follow-up were available for all 40 patients (100%). During that time period, six patients (6/40; 15%) experienced recurrence of arrhythmia.

Discussion
To our knowledge, this is the first study to examine the circumferential PVI area resulting from PFA. The main findings are: (i) Insufficient isolation areas were located most frequently in the anterior antral PV segments of the left PVs. (ii) The largest extent of insufficient isolation areas in the antral PV segments was located again on the anterior parts of both left PVs, but also in the anterior lower segment of the right inferior PV. (iii) On the other hand, enlarged LA isolation areas were located most frequently and most extensively on the PW and roof region of both LA sides. (iv) This enlarged isolation at the roof and the PW on both LA sides even resulted in a connection of both LVAs in 18 and 8%, respectively. (v) All PVs were acutely isolated.

Potential reasons for insufficient and enlarged isolation areas after pulsed-field ablation pulmonary vein isolation in our study cohort
The pentaspline PFA catheter can be deployed in essentially two configurations. The basket configuration is designed for ostial ablation and is centred into the PV ostium by its shape. The flat flower configuration is capable of ablating the PV antrum; however, its position in the PV antrum is less fixed. Due to the anatomical location of the interatrial septum in relation to the LA, a trans-septally introduced catheter will align itself toward the PW, resulting in an enlarged LA ablation of this region and insufficient ablation of the anterior antral PV segments. As there is currently only very limited integration of the PFA catheter into the available mapping systems, the catheter is navigated almost exclusively by fluoroscopic guidance. A position that is slightly too posterior can therefore easily be overseen. The observed enlarged LA isolation of the roof may be explained by guidewire positioning in superior branches of the upper PVs, which ultimately leads to alignment of the catheter system toward the roof. Simultaneously, reduced coverage of the antral PV segments on the sidewall will result.  Enlarged LA isolation found on the right sidewall is likely a result of the limited manoeuvrability of the PFA catheter due to the small distance between trans-septal puncture site and the RIPV.
Furthermore, insufficient and enlarged isolation areas can be explained by the oval shape of the PVs 16 and the circular shape of the ablation catheter system.

Comparison with previous data
A substantial amount of data, with respect to antral PVI area, is available for other single-shot devices for PVI, mostly the cryoballoon ablation system. Comparison of the available data is particularly limited, due to different low-voltage thresholds, varying freeze protocols, technical progress (different generations of the system), and lack of detailed analysis of the antral PV segments. The works of Miyazaki et al. 6 and Nagashima et al. 17 (both done with the second generation 28 mm cryoballoon) are comparable with our study cohort with respect to the low-voltage-threshold definition. In those studies, total antral PVI area was measured with 17.9 and 33.5 cm 2 , respectively. Our area of 22.2 cm 2 is consistently in between these reported values, so that in this regard a PFA-PVI seems to be similar to a cryoballoon PVI.
Data on the isolation area after pulsed-field PVI are still scarce. Kawamura et al. 9,10 published two studies with the same voltage threshold as in our study. They showed that the isolation area size did not regress between the acute (procedure end) and the chronic phase (>75 days postpulsed-field PVI). 10 Moreover, the isolation area size was similar between the PFA-PVI cohort and a comparative thermal ablation PVI cohort (radiofrequency, cryoballoon, laserballoon). 9 In contrast to our work, isolation area analysis was limited strictly to the PW, whereas, in our study, insufficient isolation areas were most commonly found in the anterior antral PV segments. Despite this limitation, the reported total PW ablation lesion size 9,10 of 11 cm 2 is compatible with our data (13 cm 2 ). Interestingly, approximately 50% of the PW area was ablated, which is in line with the enlarged LA isolation area of the PW reported in our study cohort. Recently, Gunawardene et al. 18 reported the isolation area in 20 patients undergoing a PFA-PVI procedure. Unfortunately, additional ablation lesions were created in 9 patients (PW isolation and/or mitral isthmus line), leaving only 11 patients with a PVI only procedure for comparison with our data. In addition, voltage maps were acquired with the Orion™ catheter and the Rhythmia™ mapping system and a different low-voltage cut-off of In the same study, in 5/80 of treated PVs, spontaneous conduction recovery occurred during the procedure. 18 Interestingly, although no analysis of the LVAs per antral PV segment was performed, the recovery sites were located in the anterior portions of both upper PVs. Areas which our analysis identified as typical spots of insufficient isolation areas.

Potential clinical consequences of our findings
Whether the clinical outcome is changed by an insufficient antral isolation area remains hypothetical from our work and has to be shown in larger patient cohorts. Recently published 1-year outcome data already show a high rate of PVI durability (84.8%) and clinical success rate for pulsed-field PVI (freedom from any atrial arrhythmia of 78.5%). 8 Nevertheless, the clinical benefit of a WACA approach for PVI has been shown in several studies. 2,3 Indisputable, recovery of PV conduction is the main reason for AF recurrence in paroxysmal AF patients. 19 A circumferential antral PVI area will potentially prevent PV conduction recovery and should be the endpoint of every PVI procedure. 1,20 On the other hand, enlarged LA isolation areas carry the following potential risks: (1) Collateral damage: Extending ablation to the LA, especially on the PW, may lead to life threatening complications in <0.05% of all PVI procedures. 1 Thermal damage to the oesophagus, a possible precursor of atrioesophageal fistula, has been reported in 11% of patients following a conventional RF-PVI procedure. 21 In contrast, in small clinical PFA-PVI trials, no oesophageal late gadolinium enhancement on MRI 8,22 or thermal lesions on oesophagoscopy 8 have been detected so far. (2) Damage to contractile atrial tissue: Enlarged LA thermal ablation can lead to scarring and loss of atrial contractility. However, this was not observed in a recent paper for PFA procedures. 23 (3) Risk for atrial tachycardia: Conventional thermal ablation energy leads to 'unorganized' fibrotic scarring and may increase the risk for atrial tachycardia. 18 In early clinical PFA-PVI data, only very small areas of fractionated atrial signals have been found in the ablation margins after PVI. 18 Whether this translates into reduced risk for atrial tachycardia post-PVI has to be studied in a larger patient cohorts. In our study, connecting lesions at the LA roof or the PW occurred in 18 and 8%, respectively. Apart from fractionated atrial signals, connecting lesions without conduction block or recovery of block may ultimately lead to macro-re-entry tachycardia and should therefore be avoided.

Limitations
In our study, the PFA catheter was selected based on the PV size. In most cases, the small catheter (31 mm) was used. Thus, we cannot make any reliable statements about the influence of catheter size on the resulting isolation area. The presented data are only applicable for the PFA system (Farapulse™) used in our study. Other systems, with for example a different catheter shape, electrode orientation, energy output, waveform, pulse architecture, amplitude, or duration, may behave completely different.
Since we do not routinely use voltage-mapping in other single-shot PVI procedures (e.g. cryoballoon PVI), we can only provide indirect comparison of the PV antral isolation area between different techniques (see Discussion section for details). Further comparative prospective studies are needed to analyse in detail the differences in insufficient and extensive PVI areas between the available single-shot PVI devices.

Conclusion
During mainly fluoroscopy-guided pulsed-field PVI procedures, insufficient antral isolation occurred most frequently in anterior antral PV segments. The largest extent of insufficient antral isolation areas was found in the same location, but also in the anterior lower segment of the right inferior PV. Enlarged LA isolation areas were located most frequently and most extensively on the PW and roof region of both LA sides. This enlarged isolation at the roof and the PW on both LA sides even resulted in a connection of both LVAs in 18 and 8%, respectively.
When using PFA to achieve a circumferential antral PVI, efforts should be made to enhance anterior antral PV segment and prevent PW and roof ablation. To further optimize the procedure, full integration of PFA catheter visualization into 3D-mapping systems is needed.

Supplementary material
Supplementary material is available at Europace online.

Funding
None declared.